Arginine α-ketoglutarate, also known as arginine 2-oxoglutarate, is an organic salt which possesses a number of physiological uses. Studies conducted in 1977 revealed its ability to enhance hepatic detoxification capacity when administered in high dosage to patients with liver cirrhosis. (Muting et al. (1977) MMW Munch Med Wochenschr, 119(16):535-8.) Its effects were marked by a significant decrease in the level of plasma ammonia and free serum phenols, which indicate improved oxidative decomposition of these compounds. Likewise, administration of arginine and α-ketoglutarate has also proven useful in treating ammonia intoxication and heightening liver detoxication in animal models. Not only was the survival rate found to be higher in the treatment group relative to the control, the treatment group also suffered fewer convulsive episodes.
In addition, arginine α-ketoglutarate has various uses as a source of α-ketoglutarate. By virtue of its role in the amino acid synthesis pathway, α-ketoglutarate exerts strong regulatory control over protein metabolism. Previous studies demonstrated its potency in conserving endogenous glutamine pools and increasing glutamine synthesis, which have particular benefits in clinical nutrition and metabolic care by countering trauma-induced catabolism. (Cynober (1999) Curr Opin Clin Nutr Metab Care, 2(1):33-7.) U.S. Pat. No. 5,646,187 describes the utility of α-ketoglutarate in treating critically ill patients for improving protein synthesis capacity, preserving lean body mass and maintaining energy status in skeletal muscle. Similarly, WO 89/03688 discloses the use of α-ketoglutarate to increase glutamine content in postoperative patients.
Alpha-ketoglutarate also possesses antioxidative properties, as supported by studies on hydrogen peroxide (H2O2)-induced hemolysis of human erythrocytes. The non-enzymatic oxidative decarboxylation of alpha-keto acids is shown to be involved in the hydrogen peroxide decomposition process. As part of the pathway leading to the citric acid cycle, α-ketoglutarate is crucial to energy generation. Studies in this area have yielded a significant correlation between leukocyte glutamate dehydrogenase deficiency and the presence of extrapyramidal signs, supranuclear palsy, absence of osteotendineal reflexes and neurogenic electromyographical findings. (Orsi et al. (1988) Acta Neurol Scand, 78(5):394-400.)
Furthermore, there is a significant link between genetic deficiency of glutamate dehydrogenase, an enzyme which converts glutamate to α-ketoglutarate, and certain dominantly inherited ataxias and olivopontocerebellar atrophy (OPCA). (Plaitakis et al. (1980) Ann Neurol, 7(4):297-303, Chokroverty et al. (1985) Neurology, 35(5):652-9.) Ataxia is a condition characterized by failure of motor control and/or irregularity of muscular action whereas OPCA refers to a group of ataxias characterized by progressive neurological degeneration affecting the cerebellum, the pons and the inferior olives.
In collagen synthesis, α-ketoglutarate plays an important role as one of the cofactors of prolyl hydroxylase and lysyl hydroxylase, enzymes responsible for hydroxylation of proline and lysine residues. Studies conducted on scorbutic animal models which characteristically exhibit lowered prolyl hydroxylase activity indicate that the enzyme activity could be increased by incubating homogenates with ascorbate (Vitamine C), ferrous ions, and α-ketoglutarate thereby alleviating the pathological symptoms. (Kuttan (1980) J Nutr, 110(8):1525-32.)
Alpha-ketoglutarate is also highly effective in preventing glycosylation/glycation of proteins associated with diabetic complications such as atherosclerosis, cataract formation, and retinopathy, and mere aging. Protein-bound advanced glycation endproducts (AGEs) can exert cytotoxic effects on neighboring cells and are, for example, the structural components of beta-amyloid plaques in Alzheimer's disease. Administration of α-ketoglutarate, however, attenuates the cytotoxicity of these AGEs via the compound's competitive inhibition of protein glycation and antioxidant properties. In the case of diabetic retinopathy, even careful monitoring of blood glucose levels does not necessarily preclude pathogenesis. Therefore, the intake of α-ketoglutarate is required in addition to a diabetic drug to prevent the glycation process in retinopathy.